The antibody adriamycin is widely used clinically in the management of leukemias and the treatment of various solid tumors. The major toxic reactions associated with its use include suppression of bone marrow activity, gastrointestinal distrubances, alopecia, stomatitis, and delayed cardiotoxicity leading to irreversible congestive heart failure. Adriamycin analogs and derivatives with improved therapeutic efficacy, extended spectrum of antitumor activity, or less toxicity than the parent agent therefore are of immediate clinical importance and relevance. These drug advantages are all exhibited by N-trifluoroacetyladriamycin-14-valerate (AD 32), an adriamycin analog first prepared in these laboratories and soon to be introduced into clinical trial. The present proposal is directed towards continuing and extending studies on chemical aspects of AD 32, with particular regard to structure-activity correlations, mechanism of action hypothesis, and improvements in pharmaceutical formulation, and also towards the synthesis and biological evaluation of other anthracycline analogs with perhaps different pharmacologic advantage. Semisynthetically derived adriamycin analogs incorporating changes in the C-9 hydroxyacetyl side-chain, chromophore-substitution, and/or modification or replacement of the natural glycoside, are envisioned; biological evaluation of new analogs will involve in vitro cell growth-inhibition and, where appropriate, DNA-binding studies, and in vivo rodent tumor therapy trials. The superiority of AD 32 over adriamycin clearly justifies the continued search for analogs with even greater therapeutic potential.